Cholesterol Major bile acids Cholic acid HO Primary Secondary OH OH COOH C27 dehydroxylase 7˜-Hydroxylase (12˜-hydroxylase) HO HO OH COOH Chenodeoxycholic acid Deoxycholic acid Conjugation of bile acids HO OH COOH HO OH 3 7 12 OH C O O OH C O–H CH2N H Glycine, pKa˜3.7 Taurine, pKa˜1.5 or SO2O–HN CH2CH2 H HO OH COOH Ursodeoxycholic acid HO COOH Lithocholic acid Liver Colon (bacteria) •Fig. 32.5 Structuresofthemajorprimaryandsecondarybileacidsofbile.Primarybileacidsaresynthesizedintheliver.Secondarybileacidsareproducedwhenintestinalbacteriaactonprimarybileacids.Atthebottomofthefiguretheconjugationofcholicacidwithglycineortaurineisshown.
bile acids is produced, and daily synthesis is then equal only to the minor fraction (≈10%/day, or 200–400 mg) that escapes uptake and is lost in stool (
Fig. 32.7 ). The only exception to this rule is lithocholic acid, which is preferentially sulfated in the hepatocyte rather than being conjugated with glycine or taurine. The majority of the sulfate conjugates are lost from the body after each meal because they are not substrates for asbt, thereby avoiding accumulation of a potentially toxic molecule.
Some comment should also be made with respect to the role of bile acids in whole-body cholesterol homeostasis. The pool of cholesterol in the body reflects its daily synthesis as well as the relatively minor component derived from inefficient dietary uptake, balanced against loss from the body, which can only occur in health via bile (
Fig. 32.8 ). Cholesterol can be excreted in two forms, either as the native molecule or after its conversion to bile acids. The latter account for up to a third of the cholesterol excreted per day despite enterohepatic recycling. Thus one strategy for treating hypercholesterolemia is to interrupt the enterohepatic circulation of bile acids, which drives increased conversion of cholesterol to bile acids; the bile acids are then lost from the body in feces.
As noted earlier, bile also contains cholesterol and phosphatidylcholine. Cholesterol transport across the canalicular membrane is mediated at least in part by a heterodimer of the active transporters we discussed in as participating in the efflux of cholesterol from the small intestinal epithelial cells, namely, ABC G5 and ABC G8 (see 32.1 ). Phosphatidylcholine derives from the inner leaflet of the canalicular membrane and is specifically “flipped” across the membrane by another ABC family transporter called multidrug resistance protein 3 (MDR3). Furthermore, 5.0